The percentage of the U.S. population over 65 is rapidly increasing, as is the incidence of chronic kidney disease (CKD). There is an increasing recognition that age and CKD are risk factors for acute kidney injury (AKI) and that AKI most often develops as an acute-on-chronic injury. We have characterized an age- dependent model of CKD in our laboratory, which recapitulates the increased incidence and severity of acute kidney injury in the elderly. Our data demonstrate that aging is associated with loss of the N-cadherin/?-catenin complex; the N-cadherin/?-catenin complex is a target of nephrotoxic injury; and aging is associated with an increased susceptibility of tubular epithelial cells to acute injury. Based on these data, we hypothesize that the age-dependent loss of the N-cadherin/?-catenin complex increases susceptibility to nephrotoxicity. Four Specific Aims have been designed to examine this hypothesis. In Aim 1, the link between age-related loss of N-cadherin and susceptibility to mercuric chloride, a relevant environmental nephrotoxicant, will be examined in vivo. These studies will focus on the hypothesis that that both increased injury and diminished repair from nephrotoxic injury distinguish the aged kidneys. In Aim 2, the direct relationship between N-cadherin loss and susceptibility to mercuric chloride will be examined in vitro using a number of molecular approaches, including overexpression and knockdown strategies. Aim 3 will test the hypothesis loss of ?-catenin leads to disorganization of the actin cytoskeleton via increased Arp2/3 activity and decreased formin-1 mediated nucleation of linear actin cables, predisposing the aged kidney to nephrotoxic insult. Finally, in Aim 4, we will develop an inducible, proximal tubular epithelial-specific ?-catenin knockout mouse to our hypothesis in vivo. These studies will be the first data to link expression of the cadherin/catenin complex with response to injury; the link between loss of N-cadherin/?-catenin and injury has tremendous implications in our understanding of mechanisms of toxicity. In addition, these studies address a novel pathway underlying the increased susceptibility of the aging kidney to injury. Taken together, these studies represent a significant advance in attempts to manage the increasing burden of renal disease in the expanding geriatric population. PUBLIC HEALTH RELEVANCE: Aging is associated with alterations in renal structure and function, which may predispose geriatric patients to acute kidney injury following exposure to nephrotoxicants. In these studies, we will examine changes that lead to the increased susceptibility of the aging kidney to injury.